CN103298793A - Method for the preparation of high-purity pharmaceutical intermediates - Google Patents
Method for the preparation of high-purity pharmaceutical intermediates Download PDFInfo
- Publication number
- CN103298793A CN103298793A CN2011800572293A CN201180057229A CN103298793A CN 103298793 A CN103298793 A CN 103298793A CN 2011800572293 A CN2011800572293 A CN 2011800572293A CN 201180057229 A CN201180057229 A CN 201180057229A CN 103298793 A CN103298793 A CN 103298793A
- Authority
- CN
- China
- Prior art keywords
- rosuvastatin
- formula
- crystal form
- salt
- iib
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 88
- 238000002360 preparation method Methods 0.000 title claims abstract description 57
- 239000012450 pharmaceutical intermediate Substances 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 229960000672 rosuvastatin Drugs 0.000 claims description 199
- -1 Rosuvastatin TBA salt Chemical class 0.000 claims description 175
- 239000013078 crystal Substances 0.000 claims description 125
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 99
- MSHKEMUMXTZIIT-MCBHFWOFSA-N ethyl (e,3r,5s)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CCOC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C(C)C)N=C(N(C)S(C)(=O)=O)N=C1C1=CC=C(F)C=C1 MSHKEMUMXTZIIT-MCBHFWOFSA-N 0.000 claims description 93
- 239000000203 mixture Substances 0.000 claims description 80
- 239000007787 solid Substances 0.000 claims description 62
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 57
- 239000007864 aqueous solution Substances 0.000 claims description 56
- 238000002425 crystallisation Methods 0.000 claims description 53
- 238000003756 stirring Methods 0.000 claims description 53
- 230000008025 crystallization Effects 0.000 claims description 52
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims description 38
- 239000000243 solution Substances 0.000 claims description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 37
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 35
- 230000015572 biosynthetic process Effects 0.000 claims description 29
- 150000001875 compounds Chemical class 0.000 claims description 29
- 229910052799 carbon Inorganic materials 0.000 claims description 26
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- 239000002994 raw material Substances 0.000 claims description 17
- 238000001816 cooling Methods 0.000 claims description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- 230000008569 process Effects 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000002798 polar solvent Substances 0.000 claims description 13
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 13
- 238000004458 analytical method Methods 0.000 claims description 11
- 239000000428 dust Substances 0.000 claims description 11
- 229910052791 calcium Inorganic materials 0.000 claims description 10
- 239000011575 calcium Substances 0.000 claims description 10
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical class C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 9
- 238000002441 X-ray diffraction Methods 0.000 claims description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 8
- IJHZGLLGELSZAF-OKLSWEBGSA-N tert-butyl (e,3r,5s)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C IJHZGLLGELSZAF-OKLSWEBGSA-N 0.000 claims description 8
- KUQHZGJLQWUFPU-BGRFNVSISA-L zinc;(e,3r,5s)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate Chemical compound [Zn+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O KUQHZGJLQWUFPU-BGRFNVSISA-L 0.000 claims description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- 125000001931 aliphatic group Chemical group 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 150000004292 cyclic ethers Chemical class 0.000 claims description 4
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 239000013558 reference substance Substances 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 230000005260 alpha ray Effects 0.000 claims 9
- 239000000543 intermediate Substances 0.000 abstract description 10
- 239000000047 product Substances 0.000 description 144
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 97
- 238000001035 drying Methods 0.000 description 62
- 239000012153 distilled water Substances 0.000 description 44
- YBRBMKDOPFTVDT-UHFFFAOYSA-O tert-butylammonium Chemical compound CC(C)(C)[NH3+] YBRBMKDOPFTVDT-UHFFFAOYSA-O 0.000 description 44
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 38
- 238000001914 filtration Methods 0.000 description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 34
- 239000000725 suspension Substances 0.000 description 34
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical class [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 description 22
- 238000005406 washing Methods 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 20
- 229910052786 argon Inorganic materials 0.000 description 19
- 239000007789 gas Substances 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 13
- 150000003863 ammonium salts Chemical class 0.000 description 12
- 238000004821 distillation Methods 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 12
- 235000011121 sodium hydroxide Nutrition 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 11
- 238000001704 evaporation Methods 0.000 description 11
- 150000001412 amines Chemical class 0.000 description 10
- 230000008020 evaporation Effects 0.000 description 10
- 239000012535 impurity Substances 0.000 description 10
- 239000010410 layer Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- RGEBGDYYHAFODH-DHMAKVBVSA-M sodium;(e,3r,5s)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate Chemical class [Na+].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O RGEBGDYYHAFODH-DHMAKVBVSA-M 0.000 description 7
- 239000011877 solvent mixture Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 238000000227 grinding Methods 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 159000000000 sodium salts Chemical class 0.000 description 5
- 159000000007 calcium salts Chemical class 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000012925 reference material Substances 0.000 description 4
- 238000007127 saponification reaction Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000003125 aqueous solvent Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 150000002596 lactones Chemical class 0.000 description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 3
- 238000001144 powder X-ray diffraction data Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 0 CC(C)C([C@]1C=CC(*)=CC(C*)O)=NC(N(C)S(C)(C)=O)=NC1c(cc1)ccc1F Chemical compound CC(C)C([C@]1C=CC(*)=CC(C*)O)=NC(N(C)S(C)(C)=O)=NC1c(cc1)ccc1F 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical class [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
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- 239000003637 basic solution Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
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- 238000004440 column chromatography Methods 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical class NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 238000002050 diffraction method Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000013020 final formulation Substances 0.000 description 2
- RBBOWEDMXHTEPA-UHFFFAOYSA-N hexane;toluene Chemical compound CCCCCC.CC1=CC=CC=C1 RBBOWEDMXHTEPA-UHFFFAOYSA-N 0.000 description 2
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- 239000000741 silica gel Substances 0.000 description 2
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- 239000008399 tap water Substances 0.000 description 2
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- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical class COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-O Methylammonium ion Chemical class [NH3+]C BAVYZALUXZFZLV-UHFFFAOYSA-O 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- SMXXJVJWTSJIIN-UHFFFAOYSA-N O(O)O.[Ba] Chemical compound O(O)O.[Ba] SMXXJVJWTSJIIN-UHFFFAOYSA-N 0.000 description 1
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- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- JVVXZOOGOGPDRZ-SLFFLAALSA-N [(1R,4aS,10aR)-1,4a-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthren-1-yl]methanamine Chemical class NC[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)C)C=C3CC[C@H]21 JVVXZOOGOGPDRZ-SLFFLAALSA-N 0.000 description 1
- HYSOPXHRAHXSFM-MRVPVSSYSA-N [(1s)-1-methylcyclohexa-2,4-dien-1-yl]methanamine Chemical class NC[C@@]1(C)CC=CC=C1 HYSOPXHRAHXSFM-MRVPVSSYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- CDMXXXZRZWQJQE-UHFFFAOYSA-N acetic acid;2-methylprop-2-enoic acid Chemical compound CC(O)=O.CC(=C)C(O)=O CDMXXXZRZWQJQE-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
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- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
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- QDYLMAYUEZBUFO-UHFFFAOYSA-N cetalkonium chloride Chemical compound CCCCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 QDYLMAYUEZBUFO-UHFFFAOYSA-N 0.000 description 1
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- ZICQBHNGXDOVJF-UHFFFAOYSA-N diamantane Chemical compound C1C2C3CC(C4)CC2C2C4C3CC1C2 ZICQBHNGXDOVJF-UHFFFAOYSA-N 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
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- 125000004494 ethyl ester group Chemical group 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-O ethylaminium Chemical compound CC[NH3+] QUSNBJAOOMFDIB-UHFFFAOYSA-O 0.000 description 1
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- 230000036541 health Effects 0.000 description 1
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- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000010494 opalescence Effects 0.000 description 1
- 125000001477 organic nitrogen group Chemical group 0.000 description 1
- 230000036211 photosensitivity Effects 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960004796 rosuvastatin calcium Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical class CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
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- 238000001179 sorption measurement Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
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Abstract
The present invention is related to intermediates useful in the preparation of pharmceutically acceptable salts of (+)-7-[4-(4- fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid and polymorphs of said intermediates, methods for preparation thereof and use thereof.
Description
Technical field of the present invention
The present invention relates to (+)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(methylsulfonyl-methyl-amino)-pyrimidine-5-yl for the preparation of formula (I)]-(3R, 5S)-dihydroxyl-heptan-intermediate of 6-olefin(e) acid and the preparation method of pharmacologically acceptable salts thereof,
New industrial favourable the improving one's methods and using of these intermediates.
(+)-7-[4-of formula (I) (4-fluorophenyl)-6-sec.-propyl-2-(methylsulfonyl-methyl-amino)-pyrimidine-5-yl]-(3R; 5S)-and dihydroxyl-heptan-6-olefin(e) acid is known active constituents of medicine with international generic name (International Nonpropriatary Name) Rosuvastatin, it regulates lipid metabolism effectively.Rosuvastatin is by suppressing the enzyme 2-hydroxy-2-methyl-pentanedioyl acyl coenzyme-A reductase enzyme in the liver, thus reducing cholesterol biosynthesizing rate and plasma cholesterol concentration and bring into play its activity.The form of Rosuvastatin, the especially salt of formula (I) is to be used for the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerotic medicine.
More specifically, the present invention relates to industrialization usability methods for the preparation of Rosuvastatin tertiary butyl ammonium (TBA) salt of high purity formula (III).
The method according to this invention, the Rosuvastatin TBA salt of formula (III) obtains by tert-butylamine is directly reacted in suitable solvent with raw material, and described raw material is selected from the Rosuvastatin methyl esters of formula (IIa), the Rosuvastatin ethyl ester of formula (IIb) or the Rosuvastatin tert-butyl ester of formula (IIIc).We have found that particularly suitable raw material is the crystal formation of the Rosuvastatin ester of general formula (II):
In formula (II), R represents methyl, ethyl or the tertiary butyl.
The Rosuvastatin methyl esters of formula (IIa) is provided according to another aspect of the present invention,
And the preparation method of the new crystal of the Rosuvastatin ethyl ester of formula (IIb).
According to another aspect of the present invention, provide crystal form II and the amorphous modification (modification) of the Rosuvastatin TBA salt of formula (III), it is as the reference substance in the morphological analysis test process of Rosuvastatin TBA salt.
Background technology
(+)-7-[4-of formula (I) (4-fluorophenyl)-6-sec.-propyl-2-(methylsulfonyl-methyl-amino)-pyrimidine-5-yl]-(3R; 5S)-dihydroxyl-heptan-6-olefin(e) acid (Rosuvastatin) is known compound; it has been originally presented in the European Patent Application No. 521471; for free acid form and as some pharmacologically acceptable salts, the Rosuvastatin calcium salt of formula (IV) for example
With and ammonium salt.
Rosuvastatin zinc (2:1) salt of formula V
According to disclosed preparation method in the european patent number 521471, the preparation of Rosuvastatin salt is undertaken by the Rosuvastatin ester of saponification formula (II), if desired, the Rosuvastatin salt that then will obtain thus changes into Rosuvastatin acid and Rosuvastatin salt or the Rosuvastatin free acid of the formula (I) that will directly obtain change into pharmacologically acceptable salts, preferably transforms the calcium salt of an accepted way of doing sth (IV).
Rosuvastatin is the photosensitive compounds that is easy to decompose, and therefore, has has researched and developed other method, and purpose is to obtain highly purified Rosuvastatin.
The chemical purity of the strict official standardized administration active constituents of medicine of promulgating according to hygiene control office (health authorities).Therefore, be fixed in the active constituents of medicine 0.1% according to the greatest limit of ICH governing principle-even with regard to the impurity with known chemical structure-its concentration.
In the preparation process for the production of the Rosuvastatin salt of final formulation, be extensive use of the Rosuvastatin salt that forms with amine.According to prior art, use stronger alkali to make amine not contain this salt by setting, this Rosuvastatin salt that forms with amine is changed into the acceptable basic metal of pharmacy or the alkaline earth salt of Rosuvastatin, and the salt that will obtain thus changes into an alkali metal salt usually, changes into the salt form as the activeconstituents in the final formulation then.
The International Patent Application WO of announcing 01060804 relates to crystallization ammonium, ammonium methyl, ethyl ammonium, di-alcohol ammonium, three (hydroxymethyl)-ammonium methyl, hexadecyldimethyl benzyl ammonium or 4-methoxy-benzyl-ammonium salt, by using aqueous sodium hydroxide solution that the above-mentioned Rosuvastatin ammonium salt of enumerating is changed into the Rosuvastatin sodium salt they are changed into amorphous rosuvastatin calcium salt, in second step, convert it into rosuvastain calcium (2:1) salt of formula (IV), and from the aqueous solution filtration product.Still unexposed this degree of purity of production.
The International Patent Application WO of announcing 2008038132 discloses the Rosuvastatin salt that forms with two amines.In these salt, only characterized dibenzyl ethylenediamine salt by the X-ray diffraction data.This salt by the Rosuvastatin of formula (I) or Rosuvastatin sodium salt as feedstock production.
It is the method for raw material Rosuvastatin calcium salt of preparation formula (IV) in aqueous solvent to the Rosuvastatin sodium salt that the International Patent Application WO of announcing 2008067440 discloses with vertical amine (dehydroabiethylamine) salt of the dehydrogenation of Rosuvastatin.The purity of disclosed Rosuvastatin calcium salt such as high performance liquid chromatography (HPLC) are measured in an embodiment is 99.80% and comprises the diastereomer impurity of 0.14% concentration, and it is very near threshold concentration (0.15%).
The method (wherein not producing the Rosuvastatin sodium salt) that several Rosuvastatin ammonium salts is directly changed into the Rosuvastatin calcium salt is disclosed among the International Patent Application WO of announcing 2004014872 and the WO2006136407.These are reflected in the aqueous solvent and carry out.
The International Patent Application WO of announcing 2004014872 relates to the method for using certain operational parameters to prepare the Rosuvastatin calcium salt, and this method causes filtration efficiency raising in the process of the precipitation of separated salt from water.In the method, the Rosuvastatin calcium salt of formula (IV) is available from some water-dissolubility Rosuvastatin ammonium salt (ammonium, trihydroxy methyl-ammonium methyl, methyl ammonium salt).
The International Patent Application WO of announcing 2005077916 relate to crystallization and amorphous rosuvastatin cyclohexyl-, dicyclohexyl-, sec.-propyl-, di-isopropyl-and (S)-1-methyl-benzyl-ammonium salt.By making Rosuvastatin ester, Rosuvastatin or Rosuvastain statin lactone with corresponding these salt of amine prepared in reaction and passing through recrystallization purifying.Yet method parameter is not disclosed as yet or example is used for ester or lactone as the method for raw material, therefore, can not measure the yield of this method, can not determine the quality of its product.Through the following steps the above-mentioned salt of enumerating is transformed the rosuvastain calcium of an accepted way of doing sth (IV): the Rosuvastain statin lactone that at first the Rosuvastatin ammonium salt is transformed an accepted way of doing sth (VI)
Convert it into sodium salt then, and react in aqueous medium with calcium ion source, and filter, obtain amorphous rosuvastatin calcium salt, its purity that has surpasses 99.5% (as what measure by HPLC).However, but the concentration height of the impurity of diastereomer: use disclosed method in the above-mentioned application of enumerating, the concentration of diastereomer impurity can not be brought down below about 0.25%.Yet this activeconstituents is not comply with in acceptable ICH governing principle in the world, because thus every kind of impurity is set to 0.1% with the threshold concentration of the impurity of known chemical structure.Another defective of this method is by other intermediate ammonium salt to be changed into end product in a plurality of steps.
In the International Patent Application WO of announcing 2005051921, the Rosuvastatin calcium salt is disclosed by crystallization sec.-propyl-or the purification process of cyclohexyl ammonium salt.At first the Rosuvastatin calcium salt is changed into the Rosuvastatin of formula (I), use ethyl acetate as solvent the Rosuvastatin of formula (I) to be changed into Rosuvastatin sec.-propyl-or cyclohexyl ammonium salt then.In aqueous medium, ammonium salt is changed into sodium salt then, and in aqueous solvent, sodium salt is transformed the Rosuvastatin calcium salt (2:1) of an accepted way of doing sth (I).The yield of this reaction is 73.6%, unexposed purity.
In the prior art, there are several methods of using basic hydrolysis Rosuvastatin ester class that relate to.In most of situation, use alkali metal hydroxide aqueous solution saponification ester class, obtain the Rosuvastatin an alkali metal salt.By Rosuvastatin basic metal or alkaline earth salt being transformed the Rosuvastatin acid of an accepted way of doing sth (I), obtaining ammonium salt with the amine reaction then and prepare ammonium salt.
Therefore, for example, be disclosed among International Patent Application WO 2003097614, WO2004052867 and the WO2006017357 of announcement with the Rosuvastatin methyl esters of aqueous sodium hydroxide solution hydrolyzing type (IIa).According to the International Patent Application WO of announcing 2007000121, use the Rosuvastatin methyl esters of lithium hydroxide hydrolyzing type (IIa).
The Rosuvastatin tert-butyl ester with sodium hydroxide saponification formula (IIc) is disclosed among International Patent Application WO 2006100689, WO2006106526, WO2007099561 and the WO2007125547 that announces:
Use the method for the Rosuvastatin ethyl ester of sodium hydroxide hydrolysis formula (IIb) to be disclosed in the International Patent Application WO 2007000121 of announcement.
In the International Patent Application WO of announcing 2005023778, having described with the Rosuvastatin alkyl ester is the method for feedstock production Rosuvastatin calcium salt.With sodium-, potassium-or this ester of barium-oxyhydroxide hydrolysis in alcoholic solution, evaporate this solution, salt is water-soluble, use the organic solvent extraction aqueous solution, after removing organic solvent and adding the calcium source, form calcium salt, pass through filtering separation.Yet this method proves by an example, only uses the Rosuvastatin tert-butyl ester of sodium hydroxide saponification formula (IIc).
According to the International Patent Application WO of announcing 2006136408, can be by using alkali hydrolysis Rosuvastatin C in the mixture of aprotic solvent or aprotic solvent and water
1-C
5Alkyl ester prepares amorphous rosuvastatin calcium salt.After this, calcium salt is joined in the reaction mixture, separate amorphous rosuvastatin calcium salt.In an embodiment, sodium hydroxide is used as alkali.
The crystal formation that is equivalent to Rosuvastatin ethyl ester, isopropyl ester and the tert-butyl ester of formula (IIa), (IIb) and Rosuvastatin (IIc) is disclosed in the International Patent Application WO 2005042522 of announcement separately.The crystalline modification of these ester classes characterizes by powder x-ray diffraction figure.By with silica gel, use the crystallization Rosuvastatin ethyl ester of the solvent mixture purifying crude product preparation formula (IIb) of toluene-hexane (1:1).Filter this solution, evaporation.In this manual, the crystal formation according to the Rosuvastatin ethyl ester of the formula (IIb) of the method in the above-mentioned application of enumerating preparation is called Rosuvastatin ethyl ester crystal formation I.
The International Patent Application WO of announcing 2009019211 discloses the crystalline modification of the Rosuvastatin methyl esters of formula (IIa), and it characterizes by powder x-ray diffraction figure.
In this manual, this modification is called the Rosuvastatin methyl esters crystal formation I of formula (IIa).According to prior art, by with preparation HPLC, use the Rosuvastatin methyl esters crystal formation I of the methyl esters preparation formula (IIa) of Di Iso Propyl Ether-Virahol (98.5:1.5) solvent mixture purification of crude.By the main fraction that evaporation concentration is gathered, then-20 ℃ of crystallizations 3 days, and filter.Evaporated filtrate obtains the Rosuvastatin methyl esters crystal formation I of formula (IIa) thus to doing.
The International Patent Application WO of announcing 2006136407 relates to the preparation method of amorphous rosuvastatin calcium, and this method is included under the existence of organic nitrogen(ous) base (amine, quaternary ammonium hydroxide, amidine, guanidine etc.) hydrolysis Rosuvastatin C in the mixture of water and no proton-organic solvent
1-C
5Alkyl ester.The salt with corresponding nitrogen base formation that will obtain thus by interpolation calcium cationic source changes into the Rosuvastatin calcium salt.In this application, claimed several Rosuvastatin ammonium salts, for example tetramethyleneimine, piperidines, morpholine, diamantane ammonium, N, N-dicyclohexyl ammonium, N-methyl-cyclohexyl base ammonium, uncle-octyl group ammonium.Disclose the preparation method of the representative of some ammonium salts, comprised the Rosuvastatin TBA salt of formula (III).However, do not characterize this salt by analytical data as yet.According to disclosed method, the Rosuvastatin TBA salt of formula (III) is not used as the raw material of the Rosuvastatin calcium salt of preparation formula (IV) as yet.In autoclave in the aqueous solution under about 100 ℃ of temperature hydrolysis Rosuvastatin ester class.Yet the quality of the ammonium salt that obtains thus is inferior to by obtaining from additive method well known in the prior art those.According to the difference of the quality of the amine that is used for reaction, degree of purity of production is at 94.5-98.9%, as what measure by HPLC.In this case, when using tert-butylamine, product purity is 98.4%.This purity possibly can't be improved subsequently, because transform in the process of Rosuvastatin calcium salt of an accepted way of doing sth (IV) at Rosuvastatin TBA salt, possibly can't be further purified and prior art does not still have the method for the rosuvastatin zinc salt of the Rosuvastatin calcium salt of relevant purifying formula (IV) or formula V.
In the International Patent Application WO of announcing 2007125547 and WO2008044243, disclose with the Rosuvastatin sodium salt be feedstock production formula (III) Rosuvastatin TBA salt method and be the method for the Rosuvastatin calcium salt of feedstock production formula (IV) with Rosuvastatin TBA salt, wherein use sodium salt as intermediate.This method is carried out in the aqueous solution, then by the filtering separation calcium salt.Still unexposed degree of purity of production.In International Patent Application WO 2007125547, disclose the crystalline modification of Rosuvastatin TBA salt and characterized by powder x-ray diffraction figure.In same application, also the claimed Rosuvastatin tertiary butyl-, isobutyl--and sec-butyl ammonium salt.
In the International Patent Application WO of announcing 2010082072, the easypro method of cutting down his spit of fland calcium (2:1) salt and changing into Rosuvastatin zinc (2:1) salt of formula V that use ethyl acetate-water biphasic solvent system changes into auspicious formula (IV) with the Rosuvastatin TBA salt of formula (III) is disclosed.
The purpose of our R﹠D work is to provide the industrialized process for preparing of the Rosuvastatin TBA salt that is suitable for high purity formula (III), it meets acceptable governing principle in the world, Rosuvastatin ester by conversion type (II) in the mixture that uses the organic solvent that mild reaction conditions mixes at water or water with water soluble carries out, and wherein R represents methyl, ethyl or the tertiary butyl.
According to the purpose that the invention solves us.
Well-known in the prior art, most of is that the method for raw material is undertaken by Rosuvastatin sodium salt intermediate with the Rosuvastatin ester, and the quality that the rosuvastain calcium that directly obtains by this method has is unsatisfactory.Therefore, usually sodium salt is changed into the ammonium salt that is suitable for recrystallization.Therefore, can carry out necessary purifying by making the ammonium salt intermediate recrystallization.Use sodium hydroxide that ammonium salt is changed into the Rosuvastatin sodium salt then, when reacting with the calcium cationic source, obtain the Rosuvastatin calcium salt.This method comprises several unnecessary steps-even use the most careful operation-most probable to cause impurity concentration to increase, and this is owing to the characteristic that is easy to decompose and the photosensitivity of Rosuvastatin.Therefore, usually, end product all can not satisfy the rule that relates to impurity that governing principle is listed with the ammonium salt of preparation by this way.
Summary of the invention
The present invention relates to the industrial suitable method for the preparation of Rosuvastatin tertiary butyl ammonium (TBA) salt of high purity formula (III) especially.According to this method, the raw material of the Rosuvastatin tert-butyl ester that makes the Rosuvastatin ethyl ester of Rosuvastatin methyl esters, formula (IIb) of the formula of being selected from (IIa) or formula (IIc) in the solvent that is fit to directly with the tert-butylamine reaction, separate the Rosuvastatin TBA salt of the formula (III) of formation thus.Have been found that the most advantageously the crystalline ester of formula (II) can be used as raw material, wherein R represents methyl, ethyl or the tertiary butyl.
The preparation method of new crystal of the Rosuvastatin ethyl ester of the Rosuvastatin methyl esters of formula (IIa) and formula (IIb) is provided according to another aspect of the present invention.
According to another kind of method of the present invention, the preparation method of crystal form II and amorphous rosuvastatin TBA salt is provided, they are suitable for as the reference material in the analytical test of the form of the Rosuvastatin TBA salt that relates to formula (III).
In the method for the invention, make the Rosuvastatin ester (wherein the implication of R is methyl, ethyl or the tertiary butyl) of formula (II), preferred its crystal formation, most preferably the Rosuvastatin ethyl ester crystal form II of the Rosuvastatin methyl esters crystal form II of formula (IIa) or formula (IIb) reacts in water, in polar solvent or in the mixture of itself and tertiary butyl aqueous ammonium, from product, except anhydrating, separate the Rosuvastatin TBA salt of the formula (III) that obtains thus.
Under the reaction conditions of using, estimate raw material or at least part of Rosuvastatin tert-butylamides that is converted to formula (VII) of product,
In independent purification step with its taking-up.As from well known in the prior art, ester class (in the presence of amine) or the ammonium salt of carboxylic acid are easy to change into corresponding acid amides when heating.This side reaction (if exist) can reduce the yield of main reaction and can produce and has dystectic crystalline impurities, and it is difficult to remove from Rosuvastatin TBA product.Unexpectedly, have been found that not form can the amount of detecting this by product, reaction yield surpasses 90%, and in several situations, the purity of TBA salt surpasses 99.9%.The preparation product purity is so high, and it is very unexpected self to need not to apply any purification step.
Detailed Description Of The Invention
According to an aspect, the present invention relates to the preparation method of the Rosuvastatin TBA salt of formula (III), this method comprises: the Rosuvastatin ester (wherein R represents methyl, ethyl or the tertiary butyl) that makes formula (II) polar solvent, preferably water or water and polar solvent for example in the mixture of water, methyl alcohol, acetonitrile, most preferably in acetonitrile with the tert-butylamine of 1.5-5 molar equivalent, preferred 2.0 molar equivalents the temperature of the boiling point of 10 ℃-solvent, preferably reaction 24-72 hour under 25-50 ℃ temperature, preferred about 40 hours.Then except after anhydrating, filtration product, washing obtains the Rosuvastatin TBA salt of the good and highly purified formula of yield (III) thus.In this manner, by making Rosuvastatin ester and tert-butylamine direct reaction, can produce and have 99.8-99.9% purity the Rosuvastatin TBA salt of (as what measure by HPLC), it surpasses any impurity of 0.1% threshold concentration that international governing principle and outline enumerate.Product has outstanding purity, needn't carry out recrystallization in addition.The Rosuvastatin TBA salt that obtains according to the inventive method directly is suitable for preparing rosuvastain calcium (2:1) salt or Rosuvastatin zinc (2:1) salt of anhydrous or hydrated form, and it has 99.8-99.9% purity (as what measure by HPLC).
Another advantage of the present invention is that it can carry out and not necessarily need extraction or the chromatography step of a large amount of organic solvents and manpower in single reactor.
By implementing method of the present invention, we have found that in most of situation, can obtain having the Rosuvastatin TBA product of the formula (III) of even form.Yet, carry out in the situation of fractional crystallization at the solution of the end product of formula (III), can obtain basically Rosuvastatin TBA new crystal uniformly.
The Rosuvastatin TBA salt crystal form II of formula (III) is provided according to another aspect of the present invention.
Characteristic powder X-ray-ray reflection of the Rosuvastatin TBA salt new crystal II of formula (III) is summarized in the table 1.The x-ray diffraction pattern of same substance as shown in fig. 1.
The x-ray reflection position of table 1 Rosuvastatin TBA salt [compound of formula (III)] crystal form II (2 θ ± 0.2 °) and relative intensity (〉 10%)
The measuring condition and the instrument that are used for powder x-ray diffraction method
Instrument: BRUKER D8ADVANCE powdery diffractometry meter
Ray:
Voltage: 40kV
Anodic current: 30mA
Annex:
-reflective mirror
The Soller-slit
Sample changer, transfer position
Detector: LynxEye
Measure: θ/θ scanning continuously: 4-352 θ °
Step-length: 0.02 °
Sample: do not grind, at room temperature measure
Well-known in the prior art, the crystal formation of same chemical compound can have visibly different physical chemical characteristics, for example stability, filterability, rate of drying, dissolution rate etc.In industrial preparation process, the preparation characteristic in batches that influences further preparation manipulation should be reproduced and have primary importance.This feature is very relevant with the form of drug substance or its intermediate.Therefore, the analytical test of the form of product is an important analysis task.Rosuvastatin TBA salt crystal form II can be used as the analysis reference material in the Rosuvastatin TBA salt test process of formula (III).
Similarly, in order to support analytical test, prepared the amorphous form of the Rosuvastatin TBA salt of formula (III).
The amorphous rosuvastatin TBA salt of formula (III) is provided according to another aspect of the present invention.Can be by Rosuvastatin TBA salt being dissolved in radical of saturated aliphatic alcohol with 1-4 carbon atom, preferably being dissolved in methyl alcohol and preparing amorphous rosuvastatin TBA salt, desolventizing is with solid residue drying at least 1 day at room temperature.
The powder x-ray diffraction figure of the amorphous rosuvastatin TBA salt of formula (III) as shown in Figure 2.Measuring condition is with above-mentioned relevant described identical with Rosuvastatin TBA salt crystal form II.
The Rosuvastatin TBA salt of different shape for example can be as the analytical test of the Rosuvastatin TBA salt that relates to formula (III) and the reference material the crystallography research process from Rosuvastatin TBA salt crystal formation I well known in the prior art, Rosuvastatin TBA salt new crystal II of the present invention and aforesaid new amorphous rosuvastatin TBA salt.
According to prior art, known before the powder x-ray diffraction analysis pretreatment sample for example grind and can influence powder X-ray-radionetric survey result significantly.Therefore, before test, do not carry out pre-treatment.
Those skilled in the art by reference material relatively diffractogram or identified the solid form of known chemical compound available from the signal specific of the observed value of this material, according to its powder x-ray diffraction figure and signal specific (reflection) (diffraction angle, relative intensity) thereof.The compound of this evaluation how solid-state for having (amorphous and crystallization) form is even more important.
The Rosuvastatin TBA salt crystal form II of formula (III) is presented at the X-ray diffraction signal that 18.651 ° of 2 θ has maximum strength.
The X-ray diffraction signal of Rosuvastatin TBA salt crystal form II that surpasses 50% relative intensity is as follows: 15.803 and 18.651 ° (2 θ).
The X-ray diffraction signal of Rosuvastatin salt crystal form II of formula (III) that surpasses 25% relative intensity is as follows: 11.282,15.803,18.651,19.050,19.832 and 20.512 ° (2 θ).
According to another aspect of the present invention, the preparation method of the Rosuvastatin TBA salt crystal form II of formula (III) is provided, this method comprises: (wherein R represents methyl with the Rosuvastatin ester of formula (II), ethyl or the tertiary butyl), preferably crystal formation is suspended in water, at 10-50 ℃, the aqueous solution that preferably will comprise the tert-butylamine of equimolar amount under 25 ℃ temperature joins wherein, randomly in 2-24 hour, repeat to add tert-butylamine 1-5 time in each mode of adding subsequently, add and comprise 0.1-0.5, the aqueous solution of the tert-butylamine of preferred 0.2 molar equivalent, remove precipitated solid after 72-96 hour, again through separating the Rosuvastatin TBA salt crystal form II of the formula (III) that obtains thus after the crystallization in 48-72 hour.
According to more advantageous embodiment of the present invention, the crystallization Rosuvastatin ester of formula (II) (wherein the implication of R is as above-mentioned definition) is for the preparation of Rosuvastatin TBA salt.Most preferably use the high-purity crystallized ester of formula (II).Have been found that raw material is influenced by its solid-state and form significantly.In addition, we also establish, and the quality of raw material has remarkably influenced to the purity of end product.
According to this embodiment, the Rosuvastatin ethyl ester new crystal II of the Rosuvastatin methyl esters new crystal II of formula (IIa) or formula (IIb) is particularly advantageous raw material.
The ester class of formula (II) (wherein the implication of R is as above-mentioned definition) is commercially available, as impure (90-95% chemical purity), be coloured thickness oily liquids or as the higher slightly solid of purity sometimes.For example, in european patent number 521471, the Rosuvastatin methyl esters of formula (IIa) is characterized by thickness oily matter, passes through the column chromatography purifying before further using.According to disclosed method in the International Patent Application WO of announcing 2009019211, be prepared the Rosuvastatin methyl esters that the type high performance liquid chromatography comes preparation formula (IIa) by making rough Rosuvastatin methyl esters.According to disclosed method in the International Patent Application WO of announcing 2005042522, obtain the crystallization Rosuvastatin ethyl ester of formula (IIb) by silica gel adsorption purifying, use hexane-toluene solvant mixture.
In our experimentation that is further purified about commodity Rosuvastatin methyl esters and ethyl ester, we are surprised to find that, can prepare the new crystal of every kind of ester.By making the crystallization from different solvents and solvent mixture of Rosuvastatin methyl esters, we have obtained new crystal, and it shows the higher stability of described new crystal.
Can not use chromatography or absorption method prepare the formula (IIa) of crystalline forms and Rosuvastatin ester class (IIb) this true self is very unexpected.The crystal formation of formula (IIa) and compound (IIb) especially is suitable for preparing the raw material of Rosuvastatin TBA salt.
The Rosuvastatin methyl esters new crystal II of formula (IIa) is provided according to another aspect of the present invention.The powder x-ray diffraction figure of Rosuvastatin methyl esters new crystal II as shown in Figure 3.The powder x-ray diffraction data of the new crystallization of methyl esters are summarized in the table 2.The measuring condition of powder x-ray diffraction method is identical with described those measuring conditions of Rosuvastatin TBA salt crystal form II.
The powder x-ray diffraction data of table 2 Rosuvastatin methyl esters [compound of (IIa) of formula] crystal form II (2 θ ± 0.2 °) and relative intensity (〉 5%)
| The peak | Angle | The d value | Intensity | The peak | Angle | The d value | Intensity |
| Numbering | 2-θ° | Dust | % | Numbering | 2-θ° | Dust | % |
| ? | ? | ? | ? | ? | ? | ? | ? |
| 1 | 8.721 | 10.13081 | 16.7 | 19 | 21.695 | 4.09302 | 53.7 |
| 2 | 9.371 | 9.43010 | 63.6 | 20 | 22.374 | 3.97039 | 13.3 |
| 3 | 9.681 | 9.12830 | 21.4 | 21 | 22.707 | 3.91291 | 5.2 |
| 4 | 12.071 | 7.32604 | 8.9 | 22 | 23.143 | 3.84011 | 11.6 |
| 5 | 13.776 | 6.42304 | 6.9 | 23 | 23.538 | 3.77661 | 7.1 |
| 6 | 15.261 | 5.80119 | 5.6 | 24 | 23.815 | 3.73326 | 10 |
| 7 | 15.551 | 5.69369 | 5.6 | 25 | 24.365 | 3.65023 | 32.3 |
| 8 | 15.933 | 5.55810 | 23 | 26 | 24.773 | 3.59108 | 24.6 |
| 9 | 16.519 | 5.36211 | 12.2 | 27 | 25.091 | 3.54626 | 7.7 |
| 10 | 16.660 | 5.31699 | 9.5 | 28 | 26.352 | 3.37933 | 29.2 |
| 11 | 17.471 | 5.07202 | 75.3 | 29 | 27.369 | 3.25605 | 6.7 |
| 12 | 18.042 | 4.91268 | 100 | 30 | 29.569 | 3.01864 | 6.6 |
| 13 | 18.836 | 4.70745 | 14.5 | 31 | 29.812 | 2.99458 | 7.6 |
| 14 | 19.553 | 4.53629 | 87.7 | 32 | 30.892 | 2.89228 | 5 |
| 15 | 19.827 | 4.47435 | 20.9 | 33 | 31.260 | 2.85903 | 5 |
| 16 | 20.239 | 4.38416 | 22.8 | 34 | 32.475 | 2.75484 | 8 |
| 17 | 20.675 | 4.29262 | 11.9 | 35 | 33.678 | 2.65910 | 7.6 |
| 18 | 21.254 | 4.17702 | 10.7 | ? | ? | ? | ? |
Can in observing the Rosuvastatin methyl esters crystal form II diffractogram of formula (IIa), 17.471,18.042 and 19.553 ° of 2 θ have the powder x-ray diffraction signal of high relative intensity.
The powder x-ray diffraction signal of Rosuvastatin methyl esters crystal form II of formula (IIa) with at least 50% relative intensity is as follows: 9.371,17.471,18.042,19.553 and 21.695 ° (2 θ).
The powder x-ray diffraction signal of Rosuvastatin methyl esters crystal form II of formula (IIa) with at least 25% relative intensity is as follows: 9.371,17.471,18.042,19.553,21.695,24.365 and 26.352 ° (2 θ).
According to another aspect of the present invention, provide the preparation method of the Rosuvastatin methyl esters crystal form II of formula (IIa), wherein with crystal formation I or the noncrystalline or oily liquids of the Rosuvastatin methyl esters of formula (IIa):
A) be dissolved in polar solvent, preferably be dissolved in the radical of saturated aliphatic alcohol or the N that comprise 1-4 carbon atom, dinethylformamide, most preferably be dissolved in ethanol, randomly by heating, this solution is mixed with water, and at cooling and optional crystal form II with this mixture Rosuvastatin methyl esters of separate type (IIa) after stirring at room 24-168 hour time; Or
B) crystallization from the mixture of water and polar solvent is preferably from water and the pure and mild N of radical of saturated aliphatic that comprises 1-4 carbon atom, crystallization in the mixture of dinethylformamide; And randomly with this solution after stirring at room 24-72 hour, the crystal form II of the Rosuvastatin methyl esters of separate type (IIa).
According to another aspect of the present invention, provide the Rosuvastatin ethyl ester crystal form II of formula (IIb), it characterizes by the powder x-ray diffraction figure of Fig. 4 and the diffraction data of table 3.
The measuring condition that powder x-ray diffraction is measured is with described those are identical to Rosuvastatin methyl esters crystal form II.
The powder x-ray diffraction signal with maximum intensity that can be suitable for the Rosuvastatin ethyl ester crystal form II of evaluation formula (IIb) in 17.907 and 19.419 degree, 2 θ discovery.
Can find to have the powder x-ray diffraction signal of the Rosuvastatin ethyl ester crystal form II of the formula (IIb) that surpasses 50% relative intensity at 9.238,17.313,17.907 and 19.419 degree (2 θ).
Can find to have the powder x-ray diffraction signal of the Rosuvastatin ethyl ester crystal form II of the formula (IIb) that surpasses 25% relative intensity at 9.238,9.638,16.354,17.313,17.907,19.419,20.137,21.478,24.112,24.376,24.684 and 26.030 degree (2 θ).
The powder x-ray diffraction data of table 3 Rosuvastatin ethyl ester [compound of formula (IIb)] crystal form II: diffraction angle (2 θ ± 0.2 °) and relative intensity (〉 5%)
| The peak | Angle | The d value | Intensity | The peak | Angle | The d value | Intensity |
| Numbering | 2-θ° | Dust | % | Numbering | 2-θ° | Dust | % |
| ? | ? | ? | ? | ? | ? | ? | ? |
| 1 | 8.717 | 10.13632 | 12.6 | 19 | 22.304 | 3.98270 | 19.1 |
| 2 | 9.238 | 9.56503 | 65.2 | 20 | 22.845 | 3.88962 | 12.8 |
| 3 | 9.638 | 9.16899 | 39.7 | 21 | 23.448 | 3.79084 | 14.5 |
| 4 | 11.942 | 7.40520 | 6.5 | 22 | 23.630 | 3.76213 | 17.4 |
| 5 | 13.737 | 6.44123 | 5.7 | 23 | 24.112 | 3.68803 | 34.7 |
| 6 | 15.056 | 5.87970 | 4.6 | 24 | 24.376 | 3.64866 | 29.3 |
| 7 | 15.457 | 5.72793 | 5.7 | 25 | 24.684 | 3.60385 | 25.5 |
| 8 | 15.846 | 5.58843 | 17.5 | 26 | 26.030 | 3.42042 | 37.7 |
| 9 | 16.354 | 5.41578 | 25.2 | 27 | 27.068 | 3.29152 | 5.6 |
| 10 | 17.313 | 5.11788 | 68.3 | 28 | 29.128 | 3.06330 | 10.9 |
| 11 | 17.907 | 4.94952 | 100 | 29 | 29.416 | 3.03392 | 7.7 |
| 12 | 18.553 | 4.77863 | 16.8 | 30 | 30.412 | 2.93678 | 5 |
| 13 | 19.419 | 4.56742 | 89 | 31 | 30.984 | 2.88386 | 5.9 |
| 14 | 20.137 | 4.40611 | 27.1 | 32 | 31.271 | 2.85806 | 5.5 |
| 15 | 20.574 | 4.31357 | 13.1 | 33 | 32.027 | 2.79234 | 5.1 |
| 16 | 21.005 | 4.22599 | 6.1 | 34 | 33.062 | 2.70725 | 11 |
| 17 | 21.478 | 4.13388 | 47.3 | 35 | 33.981 | 2.63611 | 5 |
| 18 | 21.775 | 4.07824 | 7.4 | ? | ? | ? | ? |
In the experimentation that makes the Rosuvastatin ethyl ester recrystallization from different solvents that relates to formula (IIb), we find, in most of situation, form Rosuvastatin ethyl ester new crystal II, have shown its advantages of higher stability.In this experiment, wherein will be suspended in the solvent long period with Rosuvastatin ethyl ester new crystal II of the present invention according to the Rosuvastatin ethyl ester polymorph of the method for WO2005042522 preparation (in this manual can called after crystal formation I), the Rosuvastatin ethyl ester is changed into crystal form II fully, confirm the high thermal stability of new polymorph.
According to another aspect of the present invention, provide the preparation method of the Rosuvastatin ethyl ester crystal form II of formula (IIb), wherein with solid crystal formation I or solid amorphous or the liquid of the Rosuvastatin ethyl ester of formula (IIb):
A) be dissolved in polar solvent, radical of saturated aliphatic alcohol, acetonitrile or the N of the preferred self-contained 1-4 carbon atom of described polar solvent, dinethylformamide, preferably be dissolved in ethanol, randomly by heating, this solution and water mixed and at cooling and the crystal form II that randomly after stirring at room 24-168 hour, separates the Rosuvastatin ethyl ester; Or
B) crystallization from the mixture of water and polar solvent is preferably from water and the radical of saturated aliphatic alcohol, acetonitrile and the N that comprise 1-4 carbon atom, crystallization in the mixture of dinethylformamide; This reaction mixture randomly stirred 24-72 hour and the Rosuvastatin ethyl ester crystal form II of separate type (IIb); Or
C) from being selected from the radical of saturated aliphatic ester that comprises 4-8 carbon atom, the radical of saturated aliphatic that comprises 4-8 carbon atom or cyclic ethers, having solvent or the crystallization from the mixture of the above-mentioned solvent of enumerating and water arbitrarily of radical of saturated aliphatic ketone, the aromatic hydrocarbon solvent of 3-6 carbon atom, this reaction mixture was randomly stirred 24-72 hour and separate Rosuvastatin ethyl ester crystal form II; Or
D) be dissolved in and be selected from the radical of saturated aliphatic ester with 4-8 carbon atom, the radical of saturated aliphatic with 4-8 carbon atom or cyclic ethers or have the aliphatic ketone of 3-6 carbon atom and the solvent of arene, and after adding saturated aliphatic hydrocarbon or the preferred hexane of alicyclic hydrocarbon, heptane or hexanaphthene, make the crystal form II crystallization of Rosuvastatin ethyl ester, and randomly this crystallization was stirred 24-72 hour and separation.
We have found that, Rosuvastatin methyl esters by using formula (IIa) in the method for the invention or the Rosuvastatin ethyl ester of formula (IIb), especially use its new crystal formation, can obtain having the Rosuvastatin TBA salt of about 99.9% unexpected highly purified formula (II).
Therefore, in the R﹠D work process that we are undertaken by the new crystal of Rosuvastatin ester class that uses exhibit stabilization to be higher than the formula (II) of known those of prior art, provide single stage method to prepare high purity Rosuvastatin TBA salt, this method is easy, good yield can be provided and be suitable for industrial applications.The Rosuvastatin TBA salt of the formula (III) that can will obtain thus according to method well known in the prior art changes into rosuvastain calcium (2:1) or Rosuvastatin zinc (2:1) salt.
Other aspects of the present invention are showed by the following example, but be the invention is not restricted to these embodiment.
The preparation of disclosed Rosuvastatin ethyl ester polymorph [the Rosuvastatin ethyl ester crystal formation I of formula (IIb)] in the International Patent Application WO of announcing 2005042522
Reference example 1
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 10cm
3Hot water makes it be cooled to 25 ℃.The product of oily matter form at first separates, in 24 hours whipping process, and progressively crystallization.Filtration product washes with water.Therefore, obtain 0.31g (62%) title compound.
Reference example 2
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 1cm
3Hot ethyl acetate adds 4.5cm when stirring
3Normal hexane.It is cooled to 25 ℃ with this mixture, and product progressively precipitates simultaneously.Cross filter solid, with normal hexane washing, drying.Therefore, obtain 0.49g (98%) title compound.
The preparation of raw material
Rosuvastatin ethyl ester polymorph [the Rosuvastatin ethyl ester crystal formation I of formula (IIb)] according to International Patent Application WO 2005042522 preparations of announcing changes into Rosuvastatin ethyl ester crystal form II
Obtain the Rosuvastatin ethyl ester crystal formation I of formula (IIb) according to disclosed method in the International Patent Application WO of announcing 2005042522.
In following recrystallization experiment, at the product of 30 ℃ of dry filters in the 100-150mbar vacuum.In all testing, the Rosuvastatin ethyl ester crystal form II of the formula (IIb) of demonstration powder x-ray diffraction figure and reflection is basically as shown in Fig. 4 and table 3.
Embodiment 1
0.50g (0.98mmol) Rosuvastatin ethyl ester crystal formation I (according to the WO2005042522 preparation) is dissolved in 1cm
3Hot ethanol drips 3cm
3Water.The product initial gross separation was oily matter, and it progressively became the mixture of crystallization and oil phase by second day.After this, add 5cm
3Water stirs this mixture 30 hours at 25 ℃.Therefore, obtain 0.47g (94%) Rosuvastatin ethyl ester crystal form II, the diffractogram of disclosed reflection and demonstration Fig. 4 in its indicator gauge 3.
Embodiment 2
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 1.5cm
3Hot 1:1 (v/v) alcohol-water solvent mixture.This solution is cooled to 25 ℃ when stirring.After 10 minutes, form dense thick suspension.Filtration product, drying.Therefore, obtain 0.38g (76%) product.
Embodiment 3
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 1cm
34:1 (v/v) hot ethanol-water mixture is cooled to 25 ℃ when stirring.Therefore, obtain dense thick suspension.Cross filter solid, drying.Therefore, obtain 0.24g (48%) product.
Embodiment 4
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 1cm
3Hot ethanol.By this mixture is cooled to 25 ℃, obtain cured mass, use 0.5cm
3Alcohol dilution is cooled to 0-5 ℃.Cross filter solid, drying.Therefore, obtain 0.30g (60%) product.
Embodiment 5
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 5cm at 25 ℃
3Ethanol divides small portion progressively to add the 12cm with 25 ℃ of temperature
3Water.This mixture becomes milky white photochromic, the product crystallization that separates when stirring.Cross filter solid, drying.Therefore, obtain 0.48g (96%) product.
Embodiment 6
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 1.5cm
3Hot 1:1 (v/v) methanol-water mixtures.After being cooled to 25 ℃, oily mixture is crystallization progressively, becomes suspension.Cross filter solid, drying.Therefore, obtain 0.46g (92%) product.
Embodiment 7
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 0.6cm
3Hot methanol.The first step is cooled to 25 ℃ with this mixture, after this is cooled to 0-5 ℃.Product progressively separates.Cross filter solid, drying.Therefore, obtain 0.34g (68%) product.
1.0g (1.96mmol) Rosuvastatin ethyl ester is dissolved in 2cm at 60 ℃
35:1 (v/v) methanol-water mixtures cools off with tap water.In 10 minutes, the beginning crystallization.After this, add the 11cm that is cooled to 0-5 ℃ again
3The mixture of same solvent is to obtain being suitable for stirred mixture.With this mixture restir 16 hours, filter drying.Therefore, obtain 0.79g (79%) product.
Embodiment 9
1.0g (1.96mmol) Rosuvastatin ethyl ester is dissolved in 2cm at 60 ℃
35:1.5 (v/v) methanol-water mixtures.By cooling off with tap water, continuously stirring begins crystallization simultaneously.After about half an hour, this mixture becomes dense thick.In this stage, use 9cm
3Same solvent mixture is diluted this mixture, stirs 20 hours at 25 ℃, stirs 5 hours at 0-5 ℃.Filter out solid, drying.Therefore, obtain 0.91g (91%) product.
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 0.6cm
3Hot methanol.Divide small portion progressively to add 1cm
3Water.Behind initial opalescence, product separates in the mode of muddiness.This mixture is cooled to 25 ℃, after 2 hours, filtering for crystallizing piece, drying.Therefore, obtain 0.47g (94%) product.
Embodiment 11
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 1.5cm at 25 ℃
3Methyl alcohol, portions progressively add 3.5cm
3Distilled water with 25 ℃ of temperature.Initial oily product becomes crystallization in half an hour.Filtration product, drying.Therefore, obtain 0.46g (92%) product.
Embodiment 12
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 0.6cm
3Hot methanol.This solution progressively is cooled to 25 ℃, in this process, drips 1.5cm
3Hexanaphthene.Product is at first with the oily isolated in form, after this grinding and crystallization during cooling.In 48 hours, obtain the product that is suitable for filtering.Cross filter solid, drying.Therefore, obtain 0.42g (84%) product.
Embodiment 13
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 0.6cm
3Hot methanol.This solution progressively is cooled to 25 ℃, drips 1.5cm simultaneously
3Normal hexane.The product initial separation is oily matter, progressively crystallization when grinding and cool off.After 48 hours, obtain the product that is suitable for filtering.Cross filter solid, drying.Therefore, obtain 0.44g (88%) product.
Embodiment 14
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 0.6cm
3Hot methanol.This solution progressively is cooled to 25 ℃, drips 1.5cm simultaneously
3Normal heptane.Product at first is separated into oily matter, crystallization when grinding and cool off.After 48 hours, obtain the product that is suitable for filtering.Cross filter solid, drying.Therefore, obtain 0.49g (98%) title product.
Embodiment 15
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 1cm
3Hot Virahol.At first this solution is cooled to 25 ℃, after this is cooled to 0-5 ℃ temperature.Product separates lentamente, this after-filtration, drying.Therefore, obtain 0.34g (68%) product.
Embodiment 16
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 1.5cm
3Hot 1:1 (v/v) isopropanol-water mixture.When being cooled to 25 ℃, oily mixture is crystallization progressively, and in further process of cooling, it becomes dense thick suspension.Use 1cm
3The same solvent mixture that is cooled to 5 ℃ is diluted this suspension.Filtration product, drying.Therefore, obtain 0.39g (78%) product.
Embodiment 17
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 1cm
3Hot Virahol.To wherein adding 1cm
3Water.Product begins with the oily isolated in form, crystallization during by second day.Cross filter solid, drying.Therefore, obtain 0.45g (90%) product.
Embodiment 18
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 0.25cm
3Hot propyl carbinol.When cooling, product begins with the oily isolated in form, subsequent crystallisation, and under 25 ℃ of temperature, it becomes dense thick suspension.Use 0.25cm
3The propyl carbinol that is cooled to 5 ℃ dilutes this suspension.Cross filter solid, drying.Therefore, obtain 0.16g (32%) product.
Embodiment 19
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 0.25cm
3Hot propyl carbinol is to wherein adding 1cm
3Water.Product in the initial stage with the oily isolated in form, crystallization during by second day.Use 5cm
3Water dilutes dense thick suspension.Cross filter solid, drying.Therefore, obtain 0.48g (96%) product.
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 0.7cm
3Hot acetonitrile.When being cooled to 25 ℃, product separates lentamente.This mixture further is cooled to 0-5 ℃ temperature.During by second day, obtain dense thick ingot.With this mixture of the dilution in acetonitrile that is cooled to 0-5 ℃ of temperature, obtain the suspension that is suitable for filtering.Cross filter solid, drying.Therefore, obtain 0.30g (60%) product.
Embodiment 21
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 2.5cm at 25 ℃
3Acetonitrile.Dropwise 5 cm progressively
3Water.Product is at first with the oily isolated in form, 2 days post crystallizations.Use 2.5cm
3Water dilutes dense fused mixture.Cross filter solid, drying.Therefore, obtain 0.44g (88%) product.
Embodiment 22
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 0.7cm
3Hot acetonitrile.When this solution is still warm, progressively drip 1.5cm
3Water.The crystallization during product to the second that separates as oily matter day at first.Filtration product, drying.Therefore, obtain 0.45g (90%) product.
Embodiment 23
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 1cm
3Hot ethyl acetate.This mixture is cooled to 25 ℃, and product separates lentamente simultaneously.By being cooled to 0-5 ℃ temperature, obtain dense thick crystalline mixture during by second day.Filtration product, drying.Therefore, obtain 0.49g (98%) product.
Embodiment 24
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 1cm
3Hot ethyl acetate progressively drips 7cm
3Normal hexane.Product is at first with the oily isolated in form, after this by at first being cooled to 25 ℃ and be cooled to 0-5 ℃ temperature and by grinding, become crystallization.Cross filter solid, drying.Therefore, obtain the product with 0.50g (100%).
Embodiment 25
0.5g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 1cm
3Hot isopropyl acetate.This solution is cooled to 25 ℃, in second step, is cooled to 0-5 ℃ of temperature.By second day, obtain dense thick ingot.Cross filter solid, drying.Therefore, obtain 0.25g (50%) product.
Embodiment 26
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 3.5cm
3Hot t-butyl methyl ether (MTBE).When cooling and grinding, product separates continuously.Use 2cm
3The MTBE that is cooled to 0-5 ℃ of temperature dilutes dense thick suspension.The product of filtering separation, drying.Therefore, obtain 0.38g (76%) product.
Embodiment 27
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 0.5cm
3Hot tetrahydrofuran (THF) (THF).When being cooled to 25 ℃, in the cooling during 0-5 ℃ of temperature, isolate product then.By second day, obtain dense thick ingot, use 0.25cm
3Be cooled to the THF dilution of 0-5 ℃ of temperature.The product of filtering separation, drying.Therefore, obtain 0.25g (50%) product.
Embodiment 28
With 0.50g (0.98mmol) Rosuvastatin ethyl ester at 1.5cm
335 ℃ of stirrings, drip 0.3cm then in the ether
3Methyl alcohol is till dissolving.Keep stirring, this mixture is cooled to 25 ℃.In this process, product separates from mixture continuously.Add 3cm then
3Ether, filtration product, drying.Therefore, obtain 0.26g (52%) product.
Embodiment 29
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 0.75cm
3Hot 2-methyl cellosolve.After this, drip 2cm
3Water.Product is at first with the oily isolated in form, crystallization during cooling.Cross filter solid, drying.Therefore, obtain 0.46g (92%) product.
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 0.75cm
3Hot 2-methyl cellosolve.Drip 1cm
3Hexanaphthene.Product is at first with the oily isolated in form, crystallization during by second day.Cross filter solid, drying.Therefore, obtain 0.46g (92%) product.
Embodiment 31
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 1cm
3Hot toluene.By cooling, product is with the gel isolated in form, and it becomes dense thick ingot in half an hour.Use 1cm
3Be cooled to this suspension of dilution with toluene of 0-5 ℃ of temperature, filter drying.Therefore, obtain 0.40g (80%) product.
Embodiment 32
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 0.5cm
3Hot acetone.During cooling, product begins to separate lentamente.Use 0.5cm
3This suspension of cold (0-5 ℃) acetone diluted.Cross filter solid, drying.Therefore, obtain 0.20g (40%) product.
Embodiment 33a
0.50g (0.98mmol) Rosuvastatin ethyl ester is dissolved in 0.5cm
3Hot acetone.After this, drip 2cm
3Water.Product is at first with the oily isolated in form, crystallization during cooling.Cross filter solid, drying.Therefore, obtain the product with 0.50g (100%).
The preparation of Rosuvastatin methyl esters [compound of formula IIa)] crystal form II
Obtained Rosuvastatin methyl esters as the formula (IIa) of raw material according to disclosed method in the european patent number 521471, by being the oily matter form after the column chromatography.In following disclosed method, at 30 ℃ of products at 100-150mbar vacuum under pressure dry filter.In all situations, obtain the crystal form II of the Rosuvastatin methyl esters of formula (IIa), its powder x-ray diffraction figure as shown in Figure 3, and the position of diffracted signal and relative intensity are as shown in table 2.
Embodiment 34
0.50g (1.0mmol) Rosuvastatin methyl esters is dissolved in 1.5cm
3Hot 1:1 (v/v) alcohol-water solvent mixture is cooled to 25 ℃ with this solution, stirs simultaneously.Product is separated into oily matter.After this, this mixture is cooled to 0-5 ℃ of temperature, stirred 48 hours, oily matter becomes ingot simultaneously.Cross filter solid, in 30 ℃ of vacuum (at 100-150mbar) drying.Therefore, obtain 0.33g (66%) crystal form II product, its powder x-ray diffraction figure as shown in Figure 3, and the position of diffracted ray and relative intensity are as shown in table 2.
Embodiment 35
0.50g (1.0mmol) Rosuvastatin methyl esters is dissolved in 0.25cm
3Hot methanol when stirring, adds 1.25cm
3Water.Separate white oil phase, it is cooled to 25 ℃, stir simultaneously.After stirring 72 hours, material becomes crystallization.Filter this mixture, dry under the condition that in embodiment 34, provides.Therefore, obtain 0.22g (44%) product, the homomorphosis of the product that obtains among the form that it has and the embodiment 34.
Embodiment 36
0.30g (0.60mmol) Rosuvastatin methyl esters is dissolved in 0.2cm
3Hot N, dinethylformamide (DMF), portions adds 2cm
3Water.Product is separated into viscosity oily agglomerate.This mixture is cooled to 25 ℃, stirs simultaneously.Stir after 48 hours, filter the crystallized product that obtains, according to the method drying described in the embodiment 34.Therefore, obtain 0.29g (97%) product, the homomorphosis of the form that it has and embodiment 34 products.
Embodiment 37
0.20g (0.40mmol) Rosuvastatin methyl esters is dissolved in 2cm
3Hot Virahol, portions adds 8cm
3Water.Product is separated into viscosity oily agglomerate.This mixture is cooled to 25 ℃.After stirring for 1 week, product becomes crystalline state.Filtering for crystallizing is according to the method drying of embodiment 34.Therefore, obtain 0.15g (75%) product, the polymorphism of the product that obtains among its polymorphism that has and the embodiment 34 is identical.
Embodiment 38
0.30g (0.60mmol) Rosuvastatin methyl esters is dissolved in 1cm at 25 ℃
3Methyl alcohol drips 3cm
3Water stirs simultaneously.Product was separated into the viscosity agglomerate, and it stirred crystallization in the phase process at 24 hours.Filtering for crystallizing is according to the method drying described in the embodiment 34.In this manner, obtain 0.24g (80%) product, the homomorphosis of the product of the form that it has and embodiment 34.
Embodiment 39
0.30g (0.60mmol) Rosuvastatin methyl esters is dissolved in 0.4cm at 25 ℃
3DMF.Adding 4cm
3Behind the water, product is separated into oil phase.Stir after 24 hours, obtain crystallized product.Filtering for crystallizing is according to the method drying of embodiment 34.Therefore, reach 0.28g (93%) product, the homomorphosis of the product of the form that it has and embodiment 34.
Be feedstock production Rosuvastatin TBA salt [compound of formula (III)] with Rosuvastatin methyl esters [compound of formula (IIa)] crystal form II
Embodiment 40
10.0g (0.020mol) Rosuvastatin methyl esters crystal form II is dissolved in 70cm
3Acetonitrile is simultaneously 25 ℃ of stirrings.In the settled solution that obtains thus, add 19.8cm
31.0M tert-butylamine (TBA) aqueous solution, each time adds 3.96cm again in 2 hours time
3The 1.0MTBA aqueous solution of part, totally 4 times.In second day morning, add 3.96cm again
3The 1.0M TBA aqueous solution of part.With this mixture restir 24 hours, evaporating solvent, add ethyl acetate, remove remaining water by component distillation.The suspension that obtains thus is cooled to 5 ℃, stirred 1 hour, filter, with cold ethyl acetate washing, drying.Therefore, obtain having 99.94% purity 10.12g (90%) white product of (as what measure by HPLC).
Embodiment 41
30.0g (0.061mol) Rosuvastatin methyl esters crystal form II is suspended in 150cm in 25 ℃ of stirrings
3Water.In the suspension that obtains thus, add 61cm
31.0M the TBA aqueous solution.After this, in 2 hours time, in this reaction mixture, add 12.2cm at every turn
3The 1.0M TBA aqueous solution of part, totally 4 times.After 16 hour reaction times, add 12.2cm again
3The 1.0M TBA aqueous solution of part was with this reaction mixture restir 24 hours.Filtration product is with cold ethyl acetate washing, drying.Therefore, obtain 28.5g (84%) and have the white product of 99.98% purity (HPLC).
Rosuvastatin ethyl ester [compound of formula (IIb)] crystal form II is feedstock production Rosuvastatin TBA salt [compound of formula (III)]
Embodiment 42
30.0g (0.059mol) Rosuvastatin ethyl ester crystal form II is dissolved in 210cm in 25 ℃ of stirrings
3Acetonitrile.In the solution that obtains thus, add 59.4cm
31.0M the TBA aqueous solution.In 2 hours time, add 12cm more then
3The 1.0M TBA aqueous solution of part, totally 4 times.In second day morning, in this reaction mixture, add 6cm again
3The 1.0M TBA aqueous solution of part.Through after 24 hour reaction times, the evaporation acetonitrile adds 200cm in the crystallization agglomerate again
3Ethyl acetate.By component distillation from the suspension that obtains thus except anhydrating.The mixture that obtains thus is cooled to 0-5 ℃ of temperature, filters, with the crystallization of cold ethyl acetate washing and filtering, drying.Therefore, obtain the white title product that 31.14g (95%) has 99.86% purity (HPLC).
Embodiment 43
2.0g (0.004mol) Rosuvastatin ethyl ester crystal form II is dissolved in 14cm
3Acetonitrile adds 7.5cm
31.0M the TBA aqueous solution.This mixture was stirred 48 hours at 25 ℃ in autoclave.After this, evaporate this reaction mixture, by removing remaining water with the ethyl acetate component distillation.The suspension that obtains thus is cooled to 0-5 ℃ of temperature, filters, with the solid of cold ethyl acetate washing and filtering, drying.Therefore, obtain 1.90g (91%) and have product as 99.86% purity of measuring by HPLC.
Embodiment 44
1.0g (0.002mol) Rosuvastatin ethyl ester crystal form II is dissolved in 7cm
3Acetonitrile adds 2.18cm
31.0M the TBA aqueous solution.Use argon gas atmosphere that this mixture is stirred under 25 ℃ and 2.5 bar pressures in autoclave.After 5 hours, add 0.6cm
31.0M the TBA aqueous solution reacted this mixture again 24 hours.Add 1cm then
31.0M the TBA aqueous solution makes reaction continue 24 hours again.Evaporate this reaction mixture, remove remaining water by using the ethyl acetate component distillation.The suspension that obtains thus is cooled to 0-5 ℃ of temperature, filters, with the solid of cold ethyl acetate washing and filtering, drying.Therefore, obtain the product that 1.90g (91%) has 99.86% purity (passing through HPLC).
Embodiment 45
10.0g (0.02mol) Rosuvastatin ethyl ester crystal form II is dissolved in 70cm at 25 ℃
3Acetonitrile adds 35.6cm
31.0M the TBA aqueous solution.This mixture was stirred 24 hours.After this add 2cm
31.0M the TBA aqueous solution was with this mixture restir 24 hours.After this according to this mixture of method version 1 aftertreatment.Therefore, obtain the product that 8.69g (80%) has 99.90%HPLC purity.
Embodiment 46
In 2.0g (0.004mol) Rosuvastatin ethyl ester crystal form II, add 4.35cm
31.0MTBA the aqueous solution.Form dense thick suspension, it was stirred 2 hours at 25 ℃.After this add 0.4cm
3, add 2.4cm after 2 hours
31.0M the TBA aqueous solution, restir 3 hours.Add 0.8cm then
31.0M the TBA aqueous solution, stirring is spent the night.Filter this mixture, by being suspended in the solid that water washing is filtered, drying.Therefore, obtain the product that 1.76g (81%) has 99.56%HPLC purity.
Embodiment 47
In 2.0g (0.004mol) Rosuvastatin ethyl ester crystal form II, add 7.95cm
31.0M the TBA aqueous solution.This suspension was stirred 48 hours at 25 ℃.Filter this mixture, use 2cm
3The solid that water washing is filtered, drying.Therefore, obtain the product that 1.94g (90%) has 98.95%HPLC purity.
Embodiment 48
30.0g (0.059mol) Rosuvastatin ethyl ester crystal form II is suspended in 120cm
3Water adds 59.4cm at 25 ℃ in stirring
31.0M the TBA aqueous solution.After this, in 2 hours time, in this reaction mixture, add 12cm again 4 times
3The 1.0M TBA aqueous solution of part.Add 6cm second day morning again
31.0M the TBA aqueous solution.This mixture was stirred 24 hours, filter drying.Therefore, obtain the product that 23.2g (71%) has 99.50%HPLC purity.
Embodiment 49
10.0g (0.02mol) Rosuvastatin ethyl ester crystal form II is suspended in 100cm
3Water by stirring, adds 19.8cm at 25 ℃
31.0M the TBA aqueous solution.After this, in 2 hours time, in this reaction mixture, add 4 times each 3.96cm again
3The 1.0M TBA aqueous solution.Second day, in 2 hours time, repeat 2 times and add 3.96cm
31.0M the TBA aqueous solution.With this mixture restir 24 hours, obtain settled solution thus.After 1 week product is precipitated from solution.Cross filter solid, drying.Therefore, obtain 7.89g (73%) product and (measure purity by HPLC: 99.51%).
Be feedstock production Rosuvastatin TBA salt [compound of formula (III)] with the Rosuvastatin tert-butyl ester [compound of formula (IIc)]
2.0g (0.004mol) the Rosuvastatin tert-butyl ester is suspended in 14cm
3Acetonitrile adds 3.7cm
31.0M the TBA aqueous solution is simultaneously 25 ℃ of stirrings.After this in 2 hours time, add 0.8cm again 5 times
3The 1.0M TBA aqueous solution of part, stirring is spent the night.With this mixture heating up to 60 ℃, stir after 4 hours then, make temperature rise to 80 ℃.After 6 hours, in 2 hours time, in this reaction mixture, add each 0.8cm again 8 times
31.0MTBA the aqueous solution.Make this mixture seethe with excitement aftertreatment again 27 hours.Evaporate this reaction mixture, remove remaining water by using the ethyl acetate component distillation.The suspension that obtains thus is cooled to 0-5 ℃ temperature, filters, with the solid of ethyl acetate washing and filtering, drying.Therefore, obtain 1.90g (92%) product (HPLC purity: 99.60%).
Embodiment 51
2.0g (0.004mol) the Rosuvastatin tert-butyl ester is suspended in 14cm
3Acetonitrile adds 13.4cm
31.0M the TBA aqueous solution is simultaneously 25 ℃ of stirrings.After this this reaction mixture is heated to 80 ℃, seethed with excitement 36 hours, evaporation is removed remaining water by using the ethyl acetate component distillation.The suspension that obtains thus is cooled to 0-5 ℃ temperature, filters, with the solid of cold ethyl acetate washing and filtering, drying.Therefore, obtain 1.90g (92%) product.This product is suspended in 19cm
3Acetonitrile is heated to 80 ℃, drips 17cm
3Virahol is till dissolving.Filter the slight opalesque solution that obtains thus, in the first step, be cooled to 25 ℃, after this when stirring, be cooled to 0-5 ℃ of temperature.After 2 hours, cross filter solid, with cold acetonitrile washing, drying.Therefore, obtain 1.70g (85%) product (HPLC purity: 99.90%).
The preparation of Rosuvastatin TBA salt [compound of formula (III)] crystal form II
Embodiment 52
5.0g (0.01mol) Rosuvastatin ethyl ester is suspended in 65cm
3Water adds 9.9cm in this suspension
31.0M the TBA aqueous solution is simultaneously 25 ℃ of stirrings.After this in 2 hours time, in this reaction mixture, add 1.98cm again 4 times
3The 1.0M TBA aqueous solution.Second day, in 2 hours time, add 2x1.98cm again 2 times
31.0M the TBA aqueous solution.Stir after 3 hours, in 2 hours time, add 2 1.98cm
31.0M the TBA aqueous solution.4 days after-filtration precipitated solid.Leave standstill filtrate, at the product of ensuing 3 days inner filtration precipitations.Therefore, obtain 1.44g (26%) product (HPLC purity: 99.84%).The powder x-ray diffraction figure of this product as shown in fig. 1.Powder x-ray diffraction position and relative intensity are summarized in the table 1.
The preparation of amorphous rosuvastatin TBA salt [compound of formula (III)]
Embodiment 53
Be dissolved in 2.5cm at 25 ℃ of 0.35g (0.69mmol) Rosuvastatin TBA salt that will prepare according to the method for embodiment 42
3Methyl alcohol.Be evaporated to the solution for vacuum that obtains thus dried.Dried residue, air-dry at 25 ℃ up to second day.Therefore, obtain 0.33g (94%) amorphous products, the powder x-ray diffraction figure that it has as shown in Figure 2.
Embodiment 54
3.0g (6mmol) Rosuvastatin methyl esters crystal form II is dissolved in 12cm at 25 ℃
3Methyl alcohol when stirring, adds 5.9cm
31.0M the TBA aqueous solution.After this, in 2 hours time, in this reaction mixture, add 1.2cm again 5 times
31.0M the TBA aqueous solution.Behind the restir 24 hours, evaporate this mixture.Therefore, obtain 3.20g (96%) amorphous products.
By Rosuvastatin TBA salt [compound of formula (III)] preparation Rosuvastatin calcium salt [compound of formula (IV)]
Embodiment 55
In room temperature 1.67g (3.0mmol) amorphous rosuvastatin TBA salt is joined 10cm
3Water and 15cm
3In the two-layer hybrid thing of ethyl acetate, the while vigorous stirring.After all solids dissolving, in 15 minutes time, Dropwise 5 time 5x1.5cm in the two-layer hybrid thing
3(5x7.5mmol) saturated calcium chloride solution.After the interpolation, this reaction mixture room temperature restir 1 hour, is separated the ethyl acetate layer on top, use 5cm
32.0M the calcium chloride solution washing is respectively washed 2 times with 5ml water at every turn.By component distillation, through the evaporation of acetic acid methacrylate layer to doing from organic layer except anhydrating, the resistates that obtains thus is dissolved in 5cm
3Dry ethyl acetate.With this solution stirring 5 minutes, be evaporated to dried at 42-45 ℃ at the 50mbar vacuum under pressure.With resistates and 6cm
3Dry hexanaphthene mixes, and this suspension was stirred 30 minutes.Cross filter solid, use 5cm
3Dry hexanaphthene washing was 50 ℃ of vacuum-dryings 7 hours.Therefore, obtain 1.30g (87%) product.
Embodiment 56
1.67g (3.0mmol) Rosuvastatin TBA salt is joined 10cm in room temperature
3Water and 15cm
3In the biphase mixture of ethyl acetate, the while vigorous stirring.After the solid dissolving, in 15 minutes time, 3x0.4g (3x2.5mmol) solid lime acetate is joined in the biphase mixture.After the interpolation, this reaction mixture room temperature restir 1 hour, is separated the top ethyl acetate layer, use 3x5cm
3Water washing.Rise distillation, extremely do dry organic layer through the vacuum-evaporation ethyl acetate layer by azeotropic.The white residue that obtains thus is dissolved in 5cm
3Dry ethyl acetate.With this solution stirring 5 minutes, evaporate at the 50mbar vacuum under pressure at 42-45 ℃.With resistates and 6cm
3Dry hexanaphthene mixes, and this suspension was stirred 30 minutes.Cross filter solid, use 5cm
3Dry hexanaphthene washing was 50 ℃ of vacuum-dryings 7 hours.After the drying, obtain 1.36g (91%) product.
By Rosuvastatin TBA salt [compound of formula (III)] preparation rosuvastatin zinc salt [compound of formula V]
Embodiment 57
In light-shading apparatus, 20-25 ℃ of temperature 27.0g (0.049mol) amorphous rosuvastatin TBA salt is dissolved in 1620cm
3Distilled water.Filter this solution, drip 20-25 ℃ of temperature then and use 80cm
39.59g (0.053mol) ZnSO of distilled water preparation
4H
2O solution.This suspension is cooled to 5-10 ℃ of temperature, filters, use 100cm
3Distilled water wash.After this, will weigh under 5-10 ℃ of temperature in the argon gas atmosphere wet product that obtains thus of 59.9g is suspended in 540cm
3Continue 41 hours in the distilled water.Cross filter solid, use distilled water wash, vacuum-drying.Therefore, obtain 33.1g (80%) title product.
Embodiment 58
In light-shading apparatus, 1.16g (0.002mol) amorphous rosuvastatin TBA salt is joined 11.7cm
3Ethyl acetate and 55cm
3In the mixture of distilled water, stir simultaneously.After this, in argon gas atmosphere, under 20-25 ℃ of temperature, drip 1.27cm
32.23M ZnSO
4The aqueous solution stirs simultaneously.After stirring in 1 hour, separate each layer, use 2x1.3cm
32.23M ZnSO
4The aqueous solution, use 1.3cm then
3The water washing organic layer.The evaporation organic layer, add ethyl acetate repeatedly after, by component distillation except the resistates that anhydrates.The suspension that cooling obtains thus filters, and uses 2cm
3The ethyl acetate washing, vacuum-drying.With 0.70g (0.0007mol) product that obtains thus by being dissolved in 8.2cm
3In argon gas stream, stirred 4 hours at 25 ℃ in the solution that the 0.76mg sodium hydroxide of distilled water is formed.Filter this mixture, the product that will wet in argon gas atmosphere is suspended in 8.2cm repeatedly
3Has basic solution with the above-mentioned same composition of enumerating again through 2 hours.Cross filter solid, use 2cm
3Basic solution washing with same composition, vacuum lucifuge drying.Therefore, obtain 0.53g (76%) title product.
Embodiment 59
In light-shading apparatus, 20-25 ℃ of temperature 6.15g (0.011mol) Rosuvastatin TBA salt is dissolved in 370cm
3Distilled water.After this in argon gas atmosphere, drip 2.15g (0.012mol) ZnSO 20-25 ℃ of temperature
4H
2O is at 17.8cm
3Solution in the distilled water.This suspension is cooled to 5-10 ℃ of temperature, filters, use 30cm
3Distilled water wash.After this, in argon gas atmosphere, under 5-10 ℃ of temperature, will wet product at 123cm
3Stirred 41 hours in the distilled water.After the filtration, use 4x25cm
3The distilled water wash solid, vacuum lucifuge drying.Therefore, obtain 4.60g (81%) title compound.
Embodiment 60
In light-shading apparatus, 20-25 ℃ of temperature 6.20g (0.0112mol) Rosuvastatin TBA salt is dissolved in 370cm
3Distilled water.After this in argon gas atmosphere, drip 2.20g (0.0122mol) ZnSO 20-25 ℃ of temperature
4H
2O is at 17.8cm
3Solution in the distilled water.This suspension is cooled to 5-10 ℃ of temperature, filters, use 30cm
3Distilled water wash.After this, in argon gas atmosphere, under 5-10 ℃ of temperature, will wet product at 125cm
3Stirred 41 hours in the distilled water.After the filtration, use 3x30cm
3The distilled water wash solid, vacuum lucifuge drying.Therefore, obtain 4.80g (84%) title product.
Embodiment 61
In light-shading apparatus, 20-25 ℃ of temperature 1.20g (0.0022mol) Rosuvastatin TBA salt is dissolved in 72cm
3Distilled water.After this in argon gas atmosphere 20-25 ℃ of temperature with 0.53g (0.003mol) ZnSO
4H
2O is at 4.4cm
3Solution in the distilled water joins in this reaction mixture.This suspension is cooled to 5-10 ℃ of temperature, filters, use 5cm
3Distilled water wash.After this, in argon gas atmosphere, under 5-10 ℃ of temperature, will wet product at 25cm
3Stirred 41 hours in the distilled water.After the filtration, use 3x5cm
3The distilled water wash solid, vacuum lucifuge drying.Therefore, obtain 0.86g (79%) title product.
Embodiment 62
In light-shading apparatus, 20-25 ℃ of temperature 7.50g (0.014mol) Rosuvastatin TBA salt is dissolved in 450cm
3Distilled water.After this in argon gas atmosphere, drip 20-25 ℃ of temperature and use 22.6cm
32.70g (0.015mol) ZnSO of distilled water preparation
4H
2O solution.After this this suspension is cooled to 5-10 ℃ of temperature, filters, use 30cm
3The distilled water wash solid.In argon gas atmosphere, under 5-10 ℃ of temperature, will weigh the wet product of 13.8g at 150cm
3Stirred 41 hours in the distilled water.After the filtration, use 3x30cm
3The distilled water wash solid, vacuum lucifuge drying.Therefore, obtain 5.95g (86%) title product.
Embodiment 63
In light-shading apparatus, 20-25 ℃ of temperature 3.50g (0.006mol) Rosuvastatin TBA salt is dissolved in 210cm
3Distilled water.After this in argon gas atmosphere, drip 20-25 ℃ of temperature and use 13cm
31.54g (0.008mol) ZnSO of distilled water preparation
4H
2O solution.This suspension is cooled to 5-10 ℃ of temperature, filters, use 15cm
3The distilled water wash solid.After this in argon gas atmosphere, under 5-10 ℃ of temperature, will weigh the wet product of 6.50g at 110cm
3Stirred 41 hours in the distilled water.After the filtration, use 3x20cm
3The distilled water wash solid, vacuum lucifuge drying.Therefore, obtain 2.65g (82%) title product.
Embodiment 64
In light-shading apparatus, 20-25 ℃ of temperature 2.90g (0.005mol) Rosuvastatin TBA salt is dissolved in 175cm
3Distilled water.After this in argon gas atmosphere, drip 1.28g (0.0068mol) ZnSO 20-25 ℃ of temperature
4H
2O is at 11cm
3Solution in the distilled water.This suspension is cooled to 5-10 ℃ of temperature, filters, use 10cm
3Distilled water wash.After this in argon gas atmosphere, under 5-10 ℃ of temperature, will weigh the wet product of 5.40g at 85cm
3Stirred 41 hours in the distilled water.After the filtration, use 3x20cm
3The distilled water wash solid, vacuum lucifuge drying.Therefore, obtain 2.30g (86%) title product.
Prepare rosuvastatin zinc salt [compound of formula V] by Rosuvastatin methyl esters [compound of formula (IIa)] crystal form II
Embodiment 65
2.0g (4.0mmol) Rosuvastatin methyl esters crystal form II is dissolved in 8cm at 25 ℃
3Methyl alcohol when stirring, under uniform temp, adds 4cm
31.0M the TBA aqueous solution.In 2 hours time, in this reaction mixture, add 0.8cm again 5 times
31.0M the TBA aqueous solution.With this compound restir 24 hours, evaporation added 20cm in resistates
3Ethyl acetate and 6cm
3Distilled water.Under 20-25 ℃ of temperature, in 10 minutes, in biphase mixture, drip 2.2cm
32.2M ZnSO
4The aqueous solution.After stirring in 1 hour, separate each layer, use 2x10cm
32.2M ZnSO
4The aqueous solution and 10cm
3The distilled water wash organic layer.The evaporation organic layer, add ethyl acetate repeatedly after, remove residual water by component distillation.The suspension that cooling obtains thus filters, and uses 2cm
3The ethyl acetate washing, vacuum-drying.Therefore, obtain 1.24g (60%) crude product, with its in argon gas atmosphere under 0-5 ℃ of temperature by 0.8mg sodium hydroxide and 8cm
3Stirred 36 hours in the aqueous solution that distilled water is formed.After this, filter this mixture, use 2cm
3Has and the soda lye wash solid of same composition as mentioned above vacuum lucifuge drying.Therefore, obtain 1.10g (89%) title product.
Embodiment 66
3.0g (6.0mmol) Rosuvastatin methyl esters crystal form II is dissolved in 12cm at 25 ℃
3Methyl alcohol when stirring, under uniform temp, adds 5.9cm
31.0M the TBA aqueous solution.After this in 2 hours time, in this reaction mixture, add 1.2cm again 5 times
31.0M the TBA aqueous solution.With this mixture restir 24 hours, evaporation was by adding 3x40cm
3Ethyl acetate is removed residual water 3 times by component distillation repeatedly.In the resistates that obtains thus, add 34cm
3Ethyl acetate and 10cm
3Distilled water.Then under 20-25 ℃ of temperature, in 10 minutes, with 3.7cm
32.2M ZnSO
4The aqueous solution joins in the biphase mixture.After stirring in 1 hour, separate each layer, use 2x10cm
32.2M ZnSO
4The aqueous solution and 10cm
3The distilled water wash organic layer.The evaporation organic layer, by use ethyl acetate repeatedly component distillation remove remaining water.Cool off this suspension, filter, use 3cm
3The ethyl acetate washing, vacuum-drying.Therefore, obtain 2.50g (81%) crude product, with its in argon gas atmosphere under 0-5 ℃ of temperature at 1.2mg sodium hydroxide in 12cm
3Stirred 36 hours in the solution of distilled water.Filter this mixture, with having and the soda lye wash of same composition as mentioned above vacuum lucifuge drying.Therefore, obtain 2.25g (90%) title product.
Claims (25)
1. the preparation method of the Rosuvastatin TBA salt of formula (III):
This method comprises: use polar solvent, and preferably water, methyl alcohol or acetonitrile, the most advantageously acetonitrile makes the Rosuvastatin ester of formula (II)
Preferred its has the solid crystal formation, and wherein in formula (II), R represents methyl, ethyl or the tertiary butyl; With the 1.5-5 molar equivalent, preferably the aqueous solution with the tert-butylamine of 2.0 molar equivalents reacts under the temperature of 10 ℃-solvent boiling point.
2. the preparation method of the crystal form II of the Rosuvastatin TBA salt of formula (III), this method comprises: with the Rosuvastatin ester of formula (II), wherein R represents methyl, ethyl or the tertiary butyl, the crystal form II of the compound of preferred formula (IIb)
Be suspended in the water; 10-50 ℃, preferably under 25 ℃ of temperature, add the aqueous solution of the tert-butylamine of equimolar amount; Randomly in 2-24 hour, add TERTIARY BUTYL AMINE 1-5 time repeatedly, undertaken by each tert-butylamine aqueous solution that adds 0.1-0.5, preferred 0.2 molar equivalent; After 72-96 hour, from this solution, remove the solid of separation; And the crystal form II that separates the Rosuvastatin TBA salt of the formula (III) that obtains thus.
3. the preparation method of the amorphous rosuvastatin TBA salt of formula (III), this method comprises: Rosuvastatin TBA salt is dissolved in the radical of saturated aliphatic alcohol with 1-4 carbon atom, preferably is dissolved in methyl alcohol; Desolventizing; And at the air-dry solid residue of room temperature.
4. the crystal form II of the Rosuvastatin TBA salt of formula (III), it has in the powder x-ray diffraction analytic process and uses CuK
αThe maximum intensity X-ray diffraction signal at 18.651 degree (+/-0.2 °) 2 θ that ray is measured.
5. the crystal form II of the Rosuvastatin TBA salt of formula (III), it has in the powder x-ray diffraction analytic process and uses CuK
αRay measure as the X-ray diffraction signal that surpasses 50% relative intensity of upper/lower positions: 15.803 and 18.651 spend (+/-0.2 °) (2 θ).
6. the crystal form II of the Rosuvastatin TBA salt of formula (III), it has in the powder x-ray diffraction analytic process and uses CuK
αThe X-ray diffraction signal that surpasses 25% relative intensity at 11.282,15.803,18.651,19.050,19.832 and 20.512 degree (+/-0.2 °) (2 θ) that ray is measured.
7. the crystal form II of the Rosuvastatin TBA salt of formula (III), it has in the powder x-ray diffraction analytic process and uses CuK
αRay measure as the X-ray diffraction signal above 5% relative intensity of upper/lower positions (2 θ ± 0.2 °):
。
8. amorphous rosuvastatin TBA salt.
9. each method of claim 1-3 is characterized in that raw material is selected from:
The crystal form II of the Rosuvastatin methyl esters of formula (IIa)
The crystal form II of the Rosuvastatin ethyl ester of formula (IIb)
And the Rosuvastatin tert-butyl ester of formula (IIc)
10. according to the application of Rosuvastatin TBA salt in preparation rosuvastain calcium (2:1) salt of the formula (III) of each preparation of claim 1-3.
11. the application of Rosuvastatin TBA salt in preparation Rosuvastatin zinc (2:1) salt according to the formula (III) of each preparation of claim 1-3.
12. the crystal form II of the Rosuvastatin methyl esters of formula (IIa), it has use CuK in powder x-ray diffraction method
αThe strongest diffracted signal that ray is measured: 17.471,18.042 and 19.553 degree (2 θ ± 0.2 degree).
13. the crystal form II of the Rosuvastatin methyl esters of formula (IIa), it has use CuK in powder x-ray diffraction method
αRay measure as the diffracted signal that surpasses 50% relative intensity of upper/lower positions: 9.371,17.471,18.042,19.553 and 21.695 degree (2 θ ± 0.2 is spent).
14. the crystal form II of the Rosuvastatin methyl esters of formula (IIa), it has the following CuK that uses in powder x-ray diffraction method
αRay measure at the diffracted signal with at least 25% relative intensity as upper/lower positions: 9.371,17.471,18.042,19.553,21.695,24.365 and 26.352 degree (2 θ ± 0.2 is spent).
15. the crystal form II of the Rosuvastatin methyl esters of formula (IIa), it has the following CuK that uses in powder x-ray diffraction method
αRay measure at the diffracted signal as upper/lower positions: (2 θ ± 0.2 is spent; Relative intensity〉5%):
。
16. the preparation method of the crystal form II of the Rosuvastatin methyl esters of formula (IIa), this method comprises:
A) crystal formation I, noncrystalline solid or the liquid with the Rosuvastatin methyl esters of formula (IIa) is dissolved in polar solvent, preferably be dissolved in the radical of saturated aliphatic alcohol or the N that comprise 1-4 carbon atom, dinethylformamide the most advantageously is dissolved in ethanol, is randomly undertaken by heating; Mix the solution obtain thus and water and in cooling with choose the crystal form II that after stirring at room 24-168 hour time, separates the Rosuvastatin methyl esters wantonly; Or
B) make the crystal formation I of the Rosuvastatin methyl esters of formula (IIa), noncrystalline solid or liquid crystallization from the mixture of polar solvent and water, preferably crystallization or from N from the mixture of the radical of saturated aliphatic alcohol and water that comprises 1-4 carbon atom, crystallization in the mixture of dinethylformamide and water; Randomly with this mixture at stirring at room 24-72 hour; And the crystal form II that separates the Rosuvastatin methyl esters.
17. the crystal form II of the Rosuvastatin ethyl ester of formula (IIb), it has use CuK in powder x-ray diffraction method
αRay measure at the strongest diffracted signal as upper/lower positions: 17.907 and 19.419 degree (2 θ ± 0.2 is spent).
18. the crystal form II of the Rosuvastatin ethyl ester of formula (IIb), it has use CuK in powder x-ray diffraction method
αRay measure as the diffracted signal that surpasses 50% relative intensity of upper/lower positions: 9.238,17.313,17.907 and 19.419 degree (2 θ ± 0.2 is spent).
19. the crystal form II of the Rosuvastatin ethyl ester of formula (IIb), it has use CuK in powder x-ray diffraction method
αRay measure as the diffracted signal that surpasses 25% relative intensity of upper/lower positions: 9.238,9.638,16.354,17.313,17.907,19.419,20.137,21.478,24.112,24.376,24.684 and 26.030 degree (2 θ ± 0.2 is spent).
20. the crystal form II of the Rosuvastatin ethyl ester of formula (IIb), it has the following CuK that uses in powder x-ray diffraction method
αRay measure at the diffracted signal as upper/lower positions: (2 θ ± 0.2 is spent; Relative intensity〉5%):
。
21. the preparation method of the crystal form II of the Rosuvastatin ethyl ester of formula (IIb), this method comprises:
A) crystal formation I, noncrystalline solid or the liquid with the Rosuvastatin methyl esters of formula (IIb) is dissolved in polar solvent, preferably be dissolved in the radical of saturated aliphatic alcohol, acetonitrile or the N that comprise 1-4 carbon atom, dinethylformamide the most advantageously is dissolved in ethanol, is randomly undertaken by heating; Mix this solution and water and at cooling and the crystal form II of the Rosuvastatin ethyl ester of separate type (IIb) behind this mixture of stirring at room randomly; Or
B) make the crystal formation I of the Rosuvastatin methyl esters of formula (IIb), noncrystalline solid or liquid crystallization from the mixture of polar solvent and water, preferably from water and comprise crystallization the mixture of radical of saturated aliphatic alcohol of 1-4 carbon atom, crystallization or from water and N from the mixture of water and acetonitrile, crystallization in the mixture of dinethylformamide; And the crystal form II of the Rosuvastatin methyl esters of separate type (IIb) after stirring at room randomly; Or
C) make the crystallization from the mixture that the radical of saturated aliphatic ester with 4-8 carbon atom, the radical of saturated aliphatic with 4-8 carbon atom or cyclic ethers, the aliphatic ketone with 3-6 carbon atom or aromatic hydrocarbon or itself and water form of the crystal formation I of the Rosuvastatin methyl esters of formula (IIb), noncrystalline solid or liquid, and randomly after stirring at room, the crystal form II of the Rosuvastatin ethyl ester of separate type (IIb); Or
D) crystal formation I, noncrystalline solid or the liquid with the Rosuvastatin methyl esters of formula (IIb) is dissolved in the aliphatic ester with 4-8 carbon atom, the aliphatic series with 4-8 carbon atom or cyclic ethers or has the aliphatic ketone of 3-6 carbon atom or the solvent of fragrant type, and after adding aliphatic hydrocrbon or the preferred hexane of alicyclic hydrocarbon, heptane or hexanaphthene, make the crystal form II crystallization of the Rosuvastatin ethyl ester of formula (IIb), and randomly after stirring at room, separate the crystal form II of Rosuvastatin ethyl ester.
22. each the application of crystallization Rosuvastatin methyl esters in the Rosuvastatin TBA of preparation formula (III) salt of formula (IIa) of claim 12-15.
23. each the application of crystallization Rosuvastatin ethyl ester in the Rosuvastatin TBA of preparation formula (III) salt of formula (IIb) of claim 17-20.
24. each the crystal form II of Rosuvastatin TBA salt of formula (III) of claim 4-7 is as analyzing the application of reference substance in the X-radiocrystallgraphy of Rosuvastatin TBA salt is analyzed.
25. the amorphous rosuvastatin TBA salt of the formula of claim 8 (III) is as the application of the analysis reference substance in the analytical test, it is advantageously used in the powder X-ray-radiocrystallgraphy analysis of Rosuvastatin TBA salt.
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| HU1000637A HU230987B1 (en) | 2010-11-29 | 2010-11-29 | Process for the preparation of pharmaceutical intermediates with high purity |
| HUP1000637 | 2010-11-29 | ||
| PCT/HU2011/000113 WO2012073055A1 (en) | 2010-11-29 | 2011-11-29 | Method for the preparation of high-purity pharmaceutical intermediates |
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| EP (1) | EP2646420A1 (en) |
| JP (1) | JP2013543884A (en) |
| CN (1) | CN103298793B (en) |
| AU (1) | AU2011334661A1 (en) |
| BR (1) | BR112013013169A2 (en) |
| CA (1) | CA2818314A1 (en) |
| EA (1) | EA029079B1 (en) |
| HU (1) | HU230987B1 (en) |
| IL (1) | IL226301A0 (en) |
| MX (1) | MX2013005961A (en) |
| NZ (1) | NZ610765A (en) |
| UA (1) | UA112423C2 (en) |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106531756A (en) * | 2016-10-28 | 2017-03-22 | 中国计量科学研究院 | Detector anode device |
| CN110483412A (en) * | 2019-09-17 | 2019-11-22 | 安徽省庆云医药股份有限公司 | A kind of synthetic method of the Rosuvastatin tert-butyl ester |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU227696B1 (en) * | 2006-04-13 | 2011-12-28 | Egyt Gyogyszervegyeszeti Gyar | Zinc salt of rosuvastatin, process for its preparation and pharmaceutical compositions containing it |
| HU229260B1 (en) * | 2010-11-29 | 2013-10-28 | Egis Gyogyszergyar Nyrt | Process for preparation of rosuvastatin salts |
| CN103709107B (en) * | 2012-09-29 | 2016-04-20 | 安徽省庆云医药化工有限公司 | New crystal of Rosuvastatin methyl esters and preparation method thereof |
| CN103848790B (en) * | 2012-12-05 | 2016-08-03 | 安徽省庆云医药化工有限公司 | Crystal formation of Rosuvastatin ester and preparation method thereof |
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- 2011-11-29 WO PCT/HU2011/000113 patent/WO2012073055A1/en active Application Filing
- 2011-11-29 EA EA201390771A patent/EA029079B1/en not_active IP Right Cessation
- 2011-11-29 EP EP11819001.6A patent/EP2646420A1/en not_active Withdrawn
- 2011-11-29 UA UAA201308185A patent/UA112423C2/en unknown
- 2011-11-29 AU AU2011334661A patent/AU2011334661A1/en not_active Abandoned
- 2011-11-29 MX MX2013005961A patent/MX2013005961A/en unknown
- 2011-11-29 US US13/990,283 patent/US9133132B2/en not_active Expired - Fee Related
- 2011-11-29 JP JP2013540447A patent/JP2013543884A/en active Pending
- 2011-11-29 NZ NZ610765A patent/NZ610765A/en not_active IP Right Cessation
- 2011-11-29 CA CA 2818314 patent/CA2818314A1/en not_active Abandoned
- 2011-11-29 CN CN201180057229.3A patent/CN103298793B/en not_active Expired - Fee Related
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106531756A (en) * | 2016-10-28 | 2017-03-22 | 中国计量科学研究院 | Detector anode device |
| CN106531756B (en) * | 2016-10-28 | 2018-05-18 | 中国计量科学研究院 | Detector anode assembly |
| CN110483412A (en) * | 2019-09-17 | 2019-11-22 | 安徽省庆云医药股份有限公司 | A kind of synthetic method of the Rosuvastatin tert-butyl ester |
| CN110483412B (en) * | 2019-09-17 | 2020-06-26 | 安徽省庆云医药股份有限公司 | Synthetic method of rosuvastatin tert-butyl ester |
Also Published As
| Publication number | Publication date |
|---|---|
| BR112013013169A2 (en) | 2020-10-13 |
| HU230987B1 (en) | 2019-08-28 |
| EP2646420A1 (en) | 2013-10-09 |
| EA201390771A1 (en) | 2013-11-29 |
| CA2818314A1 (en) | 2012-06-07 |
| IL226301A0 (en) | 2013-07-31 |
| US20130338360A1 (en) | 2013-12-19 |
| ZA201303467B (en) | 2014-07-30 |
| CN103298793B (en) | 2016-06-22 |
| NZ610765A (en) | 2015-06-26 |
| UA112423C2 (en) | 2016-09-12 |
| AU2011334661A1 (en) | 2013-06-13 |
| EA029079B1 (en) | 2018-02-28 |
| MX2013005961A (en) | 2013-07-29 |
| HU1000637D0 (en) | 2011-02-28 |
| HUP1000637A2 (en) | 2012-05-29 |
| US9133132B2 (en) | 2015-09-15 |
| JP2013543884A (en) | 2013-12-09 |
| WO2012073055A1 (en) | 2012-06-07 |
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